Use of aminosalicylates in diarrhoea-predominent irritable bowel syndrome

ABSTRACT

A method for the treatment or prophylaxis of non-inflammatory bowel diseases, diarrhoea-predominant irritable bowel syndrome or other non-specific bowel disorder is disclosed comprising administering to a patient in need of such treatment or prophylaxis an effective amount of balsalazide, or a 4-ASA or 5-ASA compound modified to include a 4-ABA side chain, or a salt or a derivative thereof, or a composition comprising balsalazide the modified compound, or a salt or a derivative thereof together with a suitable carrier. Use of balsalazide, a 4-ASA or 5-ASA compound modified to include a 4-ABA side chain, or a salt or derivative thereof, for the manufacture of a medicament for the treatment or prophylaxis of non-inflammatory bowel diseases, diarrhoea-predominant Irritable Bowel Syndrome or other non-specific bowel disorder is also disclosed.

TECHNICAL FIELD

This invention relates to the use of balsalazide for treatment ofNon-Inflammatory Bowel Disease for examplediverticulosis/diverticulitis, diarrhoea-predominant Irritable BowelSyndrome (IBS), or other non-specific bowel disorders such as IrritableBowel Syndrome (IBS) at times alternating with constipation.

BACKGROUND OF THE INVENTION

Diarrhoea-predominant IBS is a condition known to arise from non-obviouscauses. In particular, Irritable Bowel Syndrome which is defined asbeing a non-inflammatory bowel disease is known not to be caused by anydetectable infection by a pathogenic organism or organisms.

Irritable Bowel Syndrome is therefore not a form of Inflammatory BowelDisease. Inflammatory Bowel Diseases are characterised by inflammationon histology and inflammation on colonoscopy whereas Irritable BowelSyndrome shows no evidence of inflammation on colonoscopy and thehistology shows no increase in inflammatory cells. Irritable BowelSyndrome is therefore referred to as a “non specific” bowel disorderbecause there is no specific diagnostic criterion such as histology or ablood test that can diagnose it. Irritable Bowel Syndrome is onlydiagnosed when one excludes the presence of other “specific” diseases ordisorders such as Salmonella, Gastroenteritis, Campylobactergastroenteritis, Clostridium difficile infection, Giardiasis, Crohn'sdisease or Ulcerative colitis. Irritable Bowel Syndrome can bedistinguished from infective and inflammatory bowel diseases such ascolitis or Crohn's disease on culture or histological grounds andendoscopic appearances.

Irritable Bowel Syndrome is therefore a collection of symptoms such asbloating, diarrhoea, cramping, flatulence, or constipation where thereis no specific diagnostic test that turns it into a specific boweldisorder. Irritable Bowel Syndrome may therefore be diagnosed byexclusion of other specific bowel disorders. Another example of a nonspecific gastrointestinal disorder is non ulcer dyspepsia.

The large bowel in man and to a lesser extent the small bowel, containlarge concentrations of various enteric bacteria. Generally, patientswill have no pain, cramping, diarrhoea or constipation if the bacterialcontents are not infected with pathogenic strains which may colonise thebowel and remain there for prolonged periods of time. Acute infectionsand some chronic infections of the bowel flora however can causeinflammatory changes in the lining. When inflammation is visible thiscondition is called Inflammatory Bowel Disease (IBD), which can betransient or long term—for example ‘ulcerative colitis’. In some formsof IBD the visible inflammation is absent and can only be detected bytaking a biopsy and finding histological changes of inflammation. Inthis case the pathologist terms the IBD as “microscopic colitis”.

Where there are no visible colonoscopic or histological abnormalities inthe colon and when the stool tests are negative for any known infection,and yet the patient complains of symptoms referrable to the colon, suchas urgency, diarrhoea, flatulence, cramping—the diagnosis of IrritableBowel Syndrome can be made. Between 5% and 25% of the western populationin different age groups may suffer from this disorder which has alsobeen termed spastic colon, unstable colonic neurosis, spastic colitis ormucous colitis. In a classic case there is a triad of symptoms includinglow abdominal pain relieved by defecation, alternatingconstipation/diarrhoea and the passage of small calibre stools. In somepatients there may be accompanying watery diarrhoea with or withoutpain. Distension, flatulence, wind and at times nausea and headaches mayalso be accompanying systemic symptoms. At times diarrhoea alternateswith constipation.

The pathogenesis of IBS is unclear. Emotional disturbances, fibredeficiency, purgative abuse and food intolerance have been some of theimplicated aetiological agents but none have been proven nor welldemonstrated. Evidence is therefore lacking for an infective cause orauto-immunity. Conventional treatments for IBS have been unsatisfactoryas exemplified by the large number of therapies that have from time totime been recommended or trialed. These have included psychotherapy,dietary regimens, anti-spasm agents, anti-cholinergics,anti-depressants, bulking agents, various receptor antagonists,carminatives, opiates, and tranquillisers—all without substantialsuccess. Indeed there is no evidence that cure is possible. Yet IBS isone of the most common of all the gastrointestinal illnesses and thoughnot life-threatening, causes great distress especially to those severelyaffected, and may bring a feeling of frustration and helplessness, beinggenerally lifelong. In particular, diarrhoea-predominant IBS can causeincontinence in some patients and, for example, the inability of beingsure that one can reach ones employment causing some to drive from restroom to rest room on their way to work. In some patients urgency is sosevere that they can only hold their motions for a few seconds.

One treatment that has been proposed for the treatment of IBS and forother bowel diseases is the use of certain classes of aminosalicylicacids. For example Borody in U.S. Pat. No. 5,519,014 describes the useof 5-aminosalicylic acids (5-ASA compounds) for the treatment of IBS.Similarly, Lin et al (U.S. Pat. No. 6,326,364) teaches that 5-ASAcompounds can inhibit clostridia (a pathogen).

Whilst prior art methods go some way to treating IBS, there is a needfor other treatment regimes and in particular treatment regimes fornon-specific bowel disorders such as diarrhoea-predominant IBS which maynot be effectively treated by prior art methods.

OBJECT OF THE INVENTION

It is an object of the present invention, at least in preferredembodiments to overcome or substantially ameliorate at least one of theabove disadvantages or at least provide a suitable alternative.

SUMMARY OF THE INVENTION

According to a first aspect, there is provided a method for thetreatment or prophylaxis of non-inflammatory bowel diseases,diarrhoea-predominant irritable bowel syndrome or other non-specificbowel disorder comprising administering to a patient in need of suchtreatment or prophylaxis an effective amount of balsalazide or a salt ora derivative thereof or a composition comprising balsalazide or a saltor a derivative thereof together with a suitable carrier.

In one embodiment, in a sub-group of patients the method alleviatessymptoms of alternating diarrhoea and constipation type Irritable BowelSyndrome or constipation-predominant Irritable Bowel Syndrome.

According to a second aspect, there is provided a method for thetreatment or prophylaxis of non-inflammatory bowel diseases,diarrhoea-predominant irritable bowel syndrome or other non-specificbowel disorder comprising administering to a patient in need of suchtreatment or prophylaxis an effective amount of a 4-ASA or 5-ASAcompound modified to include a 4-ABA side chain, or a salt or aderivative thereof or a composition comprising the modified compound ora salt or a derivative thereof together with a suitable carrier.

According to a third aspect, there is provided use of balsalazide or asalt or derivative thereof for the manufacture of a medicament for thetreatment or prophylaxis of non-inflammatory bowel diseases,diarrhoea-predominant Irritable Bowel Syndrome or other non-specificbowel disorder.

According to a fourth aspect, there is provided use of a 4-ASA or 5-ASAcompound modified to include a 4-ABA side chain, or a salt or derivativethereof for the manufacture of a medicament for the treatment orprophylaxis of non-inflammatory bowel diseases, diarrhoea-predominantIrritable Bowel Syndrome or other non-specific bowel disorder.

According to a fifth aspect, there is provided balsalazide or a salt ora derivative thereof or a composition comprising balsalazide or a saltor a derivative thereof together with a suitable carrier when used forthe treatment or prophylaxis of non-inflammatory bowel diseases,diarrhoea-predominant Irritable Bowel Syndrome or other non-specificbowel disorder.

According to a sixth aspect, there is provided a 4-ASA or 5-ASA compoundmodified to include a 4-ABA side chain, or a salt or a derivativethereof or a composition comprising balsalazide or a salt or aderivative thereof together with a suitable carrier when used for thetreatment or prophylaxis of non-inflammatory bowel diseases,diarrhoea-predominant Irritable Bowel Syndrome or other non-specificbowel disorder.

Definitions

The following definitions are intended as general definitions and shouldin no way limit the scope of the present invention to those terms alone,but are put forth for a better understanding of the followingdescription.

Unless the context requires otherwise or specifically stated to thecontrary, integers, steps, or elements of the invention recited hereinas singular integers, steps or elements clearly encompass both singularand plural forms of the recited integers, steps or elements.

Throughout this specification, unless the context requires otherwise,the word “comprise”, or variations such as “comprises” or “comprising”,will be understood to imply the inclusion of a stated step or element orinteger or group of steps or elements or integers, but not the exclusionof any other step or element or integer or group of elements orintegers. Thus, in the context of this specification, the term“comprising” means “including principally, but not necessarily solely”.

Those skilled in the art will appreciate that the invention describedherein is susceptible to variations and modifications other than thosespecifically described. It is to be understood that the inventionincludes all such variations and modifications. The invention alsoincludes all of the steps, features, compositions and compounds referredto or indicated in this specification, individually or collectively, andany and all combinations or any two or more of said steps or features.

All the references cited in this application are specificallyincorporated by reference are incorporated herein in their entirety.However, inclusion of a specific reference herein is not intended toindicate that the reference is generally known in Australia orelsewhere.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

There is provided a method for the treatment or prophylaxis ofnon-inflammatory bowel diseases including diverticulosis/diverticulitis,diarrhoea-predominant irritable bowel syndrome or other non-specificbowel disorder including constipation, bloating, diarrhoea-constipationIBS or constipation IBS. The method comprises administering to a patientin need of such treatment or prophylaxis an effective amount ofbalsalazide or a salt or a derivative thereof or a compositioncomprising balsalazide or a salt or a derivative thereof together with asuitable carrier. The patient may be a mammal including a human.

Balsalazide corresponds to the formula

and is5[(1E)-[4-[[(2-carboxyethyl)amino]carbonyl]phenyl]azo]-2-hydroxybenzoicacid.

The present invention arose from the discovery by the inventors thattreatment of patients with non infectious bowel disorders with 5ASAcompounds such as mesalazine and olsalazine or with 4ASA compounds suchas 4-aminosalicylic acid, whether alone or in combination with 5ASAcompounds, whilst capable of suppressing symptoms in most patients withdiarrhoea-predominant IBS symptoms may be even more effective whenbalsalazide is administered alone or in combination. From clinicalexperience, it has been found by the inventor that balsalazide is muchmore powerful at suppressing the symptoms of diarrhoea-predominantIrritable Bowel Syndrome than the conventional 4ASA and 5ASA compounds.Balsalazide is better than mesalazine (5-ASA) in controlling and mayinhibit even more powerfully the symptoms of diarrhoea-predominant IBSand associated conditions enumerated below. This is unexpected. It wasnot expected that balsalazide would be capable of treatingdiarrhoea-predominant IBS as it is a very different molecule to theconventional 4ASA and 5ASA compounds. Balsalazide(5-[(1E)-[4-[[(2-carboxyethyl)amino]carbonyl]phenyl]azo-2-hydroxybenzoicacid and its sodium salt, molecular weight 437.32 (formulaC₁₇H₁₃N₃O₆Na₂.2H₂O), is composed of a 5-amino salicylic acid joined toan unusually long chain, 4-amino benzoyl-β-alanine (4-ABA). It istherefore a much larger molecule and does not belong to the samemolecular shape as mesalazine or olsalazine. The inventors noted thatbalsalazide can substantially inhibit the symptoms of diarrhoea inpatients with diarrhoea-predominant IBS. It is thought that this is dueto a large extent to the properties of the unique ‘inactive carrier’side chain (4-ABA). It is noted that the side chain together with the5-ASA potentiates inhibition of gas production, cramping, fluidsecretion, and mucus production. It appears the large side chain apartfrom the salicylate component is effective in treating diarrhoea. Inaddition, in a subgroup of patients the constipation to component of IBSmay respond to the same treatment.

Although it is reported that balsalazide is an analogue of5-aminosalicylic acid, while not wishing to be bound to any theory, inthe present method it would appear that it is not the 5-ASA group thatis functioning in diarrhoea control but the large side chain 4-ABAappears to be the active component. Other 5-ASA or 4-ASA compoundsmodified to include the 4-ABA side chain may also be effective in theinventive methods. The compounds may also be used to treat othernon-specific disorders such as non-ulcer dyspepsia.

Hence, the invention provides a method of treatment or prophylaxis ofnon-inflammatory bowel diseases, diarrhoea-predominant Irritable BowelSyndrome and other non-specific bowel disorders and their associatedsymptoms comprising a step of dosing a patient suffering therefrom withbalsalazide or a derivative or salt thereof. Other non-specific boweldisorders includes any disorder diagnosed by exclusion of other specificbowel disorders such as non-ulcer dyspepsia, alternating diarrhoea andconstipation type Irritable Bowel Syndrome, Constipation-predominantIrritable Bowel Syndrome, constipation or bloating. Non-inflammatorybowel diseases includes diverticulosis or diverticulitis.

In one embodiment, the invention provides a method for the treatment orprophylaxis of one or more of Non-inflammatory Bowel Disease,diverticulosis, diverticulitis, diarrhoea-predominant Irritable BowelSyndrome, Irritable Bowel Syndrome, bloating, diarrhoea, cramping, pain,low abdominal pain, distension, wind, flatulence, gas production, fluidsecretion, mucus production, constipation, urgency, non ulcer dyspepsia,spastic colon, unstable colonic neurosis, spastic colitis, mucouscolitis, alternating constipation/diarrhoea, incontinence, alternatingdiarrhoea and constipation type IBS or constipation IBS.

There is also provided balsalazide or a derivative or salt thereof usedfor treatment or prophylaxis of non-specific bowel disorders,particularly diarrhoea-predominant LBS.

There is also provided use of balsalazide or a derivative or saltthereof in the manufacture of medicament with said balsalazide,derivative or salt thereof as the base product with or withoutaccompanying supportive or combination active and inactive agents. Thesupportive or combination active and inactive agents may be administeredtogether with balsalazide. Such administration may or may not becoincidental administration. For example, the active agents may beadministered as a single combined composition or may be administered asseparate entities in such a manner as to have overlapping therapeuticprofiles. When administered as separate entities, the active agents maybe administered in any order as determined by the treating physician.

The supportive or combination agents may contain, amongst others,separate 5-ASA or 4-ASA compounds, such as mesalazine (5-aminosalicyclic acid), olsalazine, sulfasalazine, ipsalazide, benzalazine,para-amino salicylic acid (4-amino salicylic acid) is and pharmaceuticalacceptable salts thereof. A combination of balsalazide and olsalazine,for example together in a single capsule or separately administered, maybe used to treat both diarrhoea and constipation predominant IBS sinceolsalazine does secrete water into the bowel. Mesalazine together withbalsalazide may also be combined for diarrhoea predominant IBS. Such acombination is synergistic with amplification of the combined individualactivities. In this regard it appears that the side chain of balsalazidemay have antimicrobial activity. When combined with mesalazine, whichhas specific activity against Clostridium difficile in patients withIBS/diarrhoea who have mixed infections, balsalazide and mesalazineprovide a synergistic combination in the control of diarrhoea.

Other supportive or combination ingredients include anti-cholinergics,probiotics (eg., lactobacilli, bifodobacteria, clostridia such asClostridium butyricum, bacteroides, E coli and others), acceptableantibiotics (eg., rifamycins such as rifabutin, rifampicin, refalazil,rifaximin and others; neomycin, vancomycin, tetracyclines), anti-spasmmedications (e.g. dicyclomine), as well as various excipients.

The medicament/composition for use in the invention may be prepared bymeans known in the art for the preparation of pharmaceuticalcompositions including blending, grinding, homogenising, suspending,dissolving, emulsifying, dispersing and, where appropriate, mixing ofthe balsalazide and where present other amino-salicylic acidderivative(s), optionally together with one or more selected excipients,diluents, carriers and adjuvants and optionally together with one ormore supportive combination ingredients.

The medicament/composition of the invention may be in the form of atablet, lozenge, pill, troche, capsule, soft-gel capsule, sachet orother vehicle, elixir, powder, including lyophilised powder, solution,granule, suspension, emulsion, syrup or tincture including any formsuitable for preparation as a rectal enema. Slow-release, ordelayed-release forms may also be prepared, for example in the form ofcoated particles, multi-layer tablets or microgranules. The compositionmay also be presented in a compliance-enhancing blister pack.

Solid forms for oral administration may contain pharmaceuticallyacceptable binders, sweeteners, disintegrating agents, diluents,flavourings, coating agents, preservatives, lubricants and/or time delayagents. Suitable binders include gum acacia, gelatin, corn starch, gumtragacanth, sodium alginate, carboxymethylcellulose or polyethyleneglycol. Suitable sweeteners include sucrose, lactose, glucose, aspartameor saccharine. Suitable disintegrating agents include corn starch,methylcellulose, polyvinylpyrrolidone, xanthan gum, betonite, alginicacid or agar. Suitable diluents include lactose, sorbitol, mannitol,dextrose, kaolin, cellulose, calcium carbonate, calcium silicate ordicalcium phosphate. Suitable flavouring agents include peppermint oil,oil of wintergreen, cherry, orange or raspberry flavouring. Suitablecoating agents include polymers or copolymers of acrylic acid and/ormethacrylic acid and/or their esters, waxes, fatty alcohols, zein,shellac or gluten. Suitable preservatives include sodium benzoate,vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propylparaben or sodium bisulphite. Suitable lubricants include magnesiumstearate, stearic acid, sodium oleate, sodium chloride or talc. Suitabletime delay agents include glyceryl monostearate or glyceryl distearate.For administration as a tablet or capsule, the balsalazide may becombined in powdered or granulated form, for example by compression intoa tablet or as a filling for a capsule. Alternatively, the balsalazidemay be provided in the form of a tablet/capsule containing thebalsalazide in a microencapsulated form.

Liquid forms for oral administration may contain, in addition to theabove agents, a liquid carrier. Suitable liquid carriers include water,oils such as olive oil, peanut oil, sesame oil, sunflower oil, saffloweroil, arachis oil, coconut oil, liquid paraffin, ethylene glycol,propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol,glycerol, fatty alcohols, triglycerides or mixtures thereof.

Suspensions for oral administration may further include dispersingagents and/or suspending agents. Suitable suspending agents includesodium carboxymethylcellulose, methylcellulose,hydroxypropylmethyl-cellulose, poly-vinyl-pyrrolidone, sodium alginateor cetyl alcohol. Suitable dispersing agents include lecithin,polyoxyethylene esters of fatty acids such as stearic acid,polyoxyethylene sorbitol mono- or di-oleate, -stearate or -laurate,polyoxyethylene sorbitan mono- or di-oleate, -stearate or -laurate andthe like.

Emulsions for oral administration may further include one or moreemulsifying agents. Suitable emulsifying agents include dispersingagents as exemplified above or natural gums such as gum acacia or gumtragacanth.

Typically the disodium salt of balsalazide will be used. However anyother salt or derivative or prodrug can be used. Accordingly wherereference herein is made to balsalazide, the salt, prodrug or derivativethereof is likewise referenced.

The active ingredient may be incorporated with the pharmaceuticallyacceptable excipient/s in any suitable form, including but not limitedto tablets, lozenges, pills, troche, capsules, soft-gel capsules or aspowder in sachets. It may also be presented as granulated medication inlarger volumes in sachets. The capsules, tablets or sachets may be takenone or more times per day in balsalazide doses ranging from 100 mg to 30grams per day, for example 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600mg, 700 mg, 800 mg, 900 mg, 1000 mg, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g,9 g, 10 g, 11 g, 12 g, 13 g, 14 g, 15 g, 16 g, 17 g, 18 g, 19 g, 20 g,21 g, 22 g, 23 g, 24 g, 25 g, 26 g, 27 g, 28 g, 29 g or 30 g per day orany selected amounts within this range. Agents may be enteric coated,and may take the form of slow-release format to reach both the upper andlower bowel. In one embodiment, the balsalazide is presented in a formwhich facilitates its release in the distal small bowel. For example, ina composition of the invention, the balsalazide may be provided with anenteric coating or provided in an enteric coated release capsule, orenteric coated microencapsulated particles can be carried within acapsule of a distally-releasing amino-salicylic acid, for exampleolsalazine. Suitable materials for enteric coating are known in the artand include various synthetic resins bearing carboxyl groups, phenylsalicylate, and shellac. Examples of such enteric coating materials arepolymethacrylic acid and methacrylic acid copolymers such as methacrylicacid-acrylic acid ester copolymers; modified cellulose esters such ashydroxypropyl cellulose phthalate, hydroxypropyl methylcellulosephthalate, ethyl cellulose phthalate, methyl cellulose phthalate andmixtures thereof, cellulose acetate phthalate, hydroxypropylmethylcellulose succinate, ethyl cellulose succinate, methyl cellulosesuccinate and mixtures thereof, cellulose acetate trimellitate,cellulose ether phthalates; and polyvinyl acetate phthalate, succinateor trimellitate. In one embodiment the enteric coating is Opadry OY-P22920, available from Colorcon, 415 Moyer Blvd, West Point, Pa. 19486,United States of America. Enteric film-forming compositions aredescribed, for example, in U.S. Pat. Nos. 4,556,552 and 4,704,295, thedisclosures of which are incorporated herein by reference.

Generally for long term therapy dosage may typically commence at a lowerlevel, such as daily and build up to the desired full amount overseveral weeks, such as twice or three times daily if required. Theinvention also extends in one embodiment to multiple packages ofindividual dosages to be taken in sequence to provide such a gradualbuild up. The balsalazide may therefore be taken once, twice, threetimes a day or more frequently. In one embodiment, balsalazide isadministered twice daily. Administration may be over a period of 1 to 60days or more, including indefinitely for the lifetime of the patient.For example the balsalazide may be administered over 1, 2, 3, 4, 5, 6days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months or more.After relief of symptoms is achieved, administration of balsalazide maybe ceased, tapered, or continued for an indefinite period, for exampleincluding reduction to lower maintenance dosages.

Any suitable dosage and method of administration may be utilized, asdetermined by the treating physician. Typically this may be orally or asa rectal enema. In one embodiment, the medicament/composition may beadministered orally at a dose generally of about 3 grams balsalazide perday, this dose being the ideal dose. In another embodiment for clinicaluse, a balsalazide dose of between about 1 gram and 4 grams may be usedby patients either as a twice daily or three times daily dosage.

With the foregoing it will be appreciated that a new use has beendiscovered for balsalazide where previously no such effect has beendescribed, and that actions of balsalazide can be further potentiated,even synergistically, by the addition of further agents.

EXAMPLES

The present invention will now be described by way of example. Theexamples should not be construed as in any way limiting the scope of theinvention.

Example 1

A 34 year old female presented with a 7 year history of worseningdiarrhoea (watery 6-12/day), urgency, cramping lower abdominal pain andat times faecal incontinence. There was no clear preceding illness norantibiotic usage. She underwent numerous investigations, beginning withgeneral practitioners ordering stool cultures, blood tests, ultrasoundand CT scan examinations. With the passage of time she noticed that somefoods caused worsening of symptoms, and was told by a naturopath thatshe suffered from a ‘food allergy’. The patient restricted her diet andthis gave her some benefit in reducing the symptoms but resulted inprogressive weight loss. She consulted a gastroenterologist andunderwent endoscopic small bowel biopsy—where coeliac disease wasexcluded histologically—and colonoscopy with biopsy and further stoolcultures. All tests being non-diagnostic, she was told she had severe,diarrhoea-predominant IBS. She continued on the restricted diet, and wasreferred for counselling and hypnotherapy. Over the next 6-12 months sheprogressively lost weight with only modest control of her symptoms bythe diet. Within 2 weeks of commencing increasing doses of balsalazidefrom 1.5 gram to 3 grams per day, the stools progressively formed up,with frequency reducing to 1-2 formed stools per day. Pain wascompletely abolished, urgency disappeared and she broadened her diet. By6 weeks of treatment she regained 7 kg in weight. She continues to bevirtually completely symptom-free on balsalazide at 26 weeks.

Example 2

A 67 year old female complained of greater than 20 years of diarrhoeawith intervening constipation, abdominal bloating, pains, flatulence,and nausea with acid is reflux. She had undergone several completemedical investigations including stool tests, blood tests, X-ray imagingand colonoscopic examinations, with negative findings apart from thepresence of diverticulosis. Diagnosed as chronic IBS she triedincreasing fibre intake, controlling stress, and changing her diet, allto no avail. On commencing balsalazide 1.5 g/day and pushing the doseupwards to 4.5 g/d her diarrhoea, pains, flatulence and nausea abated.At the higher dose the constipation also disappeared. The improvementsremain sustained at 26 weeks.

Example 3

A 28 year old male was referred because of long standing diarrhoeapredominant Irritable Bowel Syndrome. This was described as being“porridgy” and sometimes watery or explosive and associated withcramping abdominal pain which passed through to his back. There was nobloating but there was marked flatulence, no nausea and some acidreflux. The man had previously been extensively investigated with testssuch as stool tests and colonoscopic examinations finding no cause forhis symptoms. Having tried a number of standard therapies the manpresented for further investigations. Because ongoing trials withpatients with diarrhoea-predominant IBS was being carried out, the malepatient commenced with a trial product (Salofalk™ oral granules, 1 gram,twice daily). Salofalk™ is a particular form of 5 Aminosalicylic acid(mesalazine) which has been found to be useful in patients with thecondition. The symptoms however continued. Even after progressivelyraising the dose to 2 grains twice daily, and then to 3 grams twicedaily, the symptoms still continued, albeit slightly reduced inseverity. The male patient was not prepared to go to a higher dose (sucha dose is also not used clinically).

The male patient was offered treatment with balsalazide in accordancewith the present invention. The balsalazide was not immediatelyavailable and after several weeks, the patients symptoms returned to asevere level. Balsalazide was commenced at a dose of 750 mg twice dailyand slowly raised to 1.5 grams twice daily. Improvement in symptoms wasdramatic and far outweighed the slight improvement with the higher dosesof Salofalk™ granules. To attempt to completely control the manssymptoms, the patient was treated with a dose of 3 grams balsalazidetwice daily (gram equivalent to Salofalk™). The patients symptomslargely disappeared. The patient had two formed stools per day withoutany urgency or flatulence and was able to eat foods he previously wouldnot have considered ingesting. The improvements were sustained at fourmonths follow up.

This example shows clinically the difference between the use of standardmesalazine and the use of balsalazide in accordance the invention indiarrhoea-predominant IBS.

INDUSTRIAL APPLICABILITY

The present invention relates to a method of treating or preventingnon-inflammatory bowel diseases, diarrhoea-predominant irritable bowelsyndrome or other non-specific bowel disorders.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein.

1-13. (canceled)
 14. A method for the treatment or prophylaxis ofdiarrhoea-predominant irritable bowel syndrome comprising administeringto a human patient in need of such treatment or prophylaxis from about500 mg to about 6 grams of balsalazide or a salt thereof and rifaximin.15. A method for the treatment or prophylaxis of alternating diarrhoeaand constipation type irritable bowel syndrome comprising administeringto human a patient in need of such treatment or prophylaxis from about500 mg to about 6 grams of balsalazide or a salt thereof and rifaximin.16. A method for the treatment or prophylaxis ofconstipation-predominant type irritable bowel syndrome comprisingadministering to a human patient in need of such treatment orprophylaxis from about 500 mg to about 6 grams of balsalazide or a saltthereof and rifaximin.
 17. The method of claim 14, wherein the disodiumsalt of balsalazide is administered.
 18. The method of claim 15, whereinthe disodium salt of balsalazide is administered.
 19. The method ofclaim 16, wherein the disodium salt of balsalazide is administered. 20.The method of claim 14, wherein the balsalazide is administered orally.21. The method of claim 15, wherein the balsalazide is administeredorally.
 22. The method of claim 16, wherein the balsalazide isadministered orally.
 23. The method of claim 17, wherein the balsalazideis administered orally.
 24. The method of claim 18, wherein thebalsalazide is administered orally.
 25. The method of claim 19, whereinthe balsalazide is administered orally.
 26. The method of claim 23,wherein from about 1 gram to about 4 grams of balsalazide isadministered.
 27. The method of claim 24, wherein from about 1 gram toabout 4 grams of balsalazide is administered.
 28. The method of claim25, wherein from about 1 gram to about 4 grams of balsalazide isadministered.
 29. The method of claim 26, wherein from about 3 grams ofbalsalazide is administered.
 30. The method of claim 27, wherein fromabout 3 grams of balsalazide is administered.
 31. The method of claim28, wherein from about 3 grams of balsalazide is administered.
 32. Themethod of claim 14, wherein the balsalazide is administered twice orthree times daily.
 33. The method of claim 15, wherein the balsalazideis administered twice or three times daily.
 34. The method of claim 16,wherein the balsalazide is administered twice or three times daily. 35.The method of claim 26, wherein the balsalazide is administered twice orthree times daily.
 36. The method of claim 27, wherein the balsalazideis administered twice or three times daily.
 37. The method of claim 28,wherein the balsalazide is administered twice or three times daily. 38.The method of claim 29, wherein the balsalazide is administered twice orthree times daily.
 39. The method of claim 30, wherein the balsalazideis administered twice or three times daily.
 40. The method of claim 31,wherein the balsalazide is administered twice or three times daily.